Spontaneous Development of IgM Anti‐Cocaine Antibodies in Habitual Cocaine Users: Effect on IgG Antibody Responses to a Cocaine Cholera Toxin B Conjugate Vaccine

Abstract

Background and Objectives In cocaine vaccine studies, only a minority of subjects made strong antibody responses. To investigate this issue, IgG and IgM antibody responses to cocaine and to cholera toxin B (CTB—the carrier protein used to enhance immune responses to cocaine) were measured in sera from the 55 actively vaccinated subjects in a Phase IIb randomized double-blind placebo-controlled trial (TA-CD 109). Methods Isotype specific ELISAs were used to measure IgG and IgM anti-cocaine and anti-CTB antibody in serial samples collected prior to and at intervals after immunization. We assessed IgG anti-cocaine responses of patients with pre-vaccination IgM anti-cocaine antibodies. Competitive inhibition ELISA was used to evaluate antibody specificity. Results and Conclusions Before immunization, 36/55 subjects had detectable IgM antibodies to cocaine, and 9 had IgM levels above the 95% confidence limit of 11 µg/ml. These nine had significantly reduced peak IgG anti-cocaine responses at 16 weeks, and all were below the concentration (40 µg/ml) considered necessary to discourage recreational cocaine use. The IgG anti-CTB responses of these same subjects were also reduced. Scientific Significance Subjects who develop an IgM antibody response to cocaine in the course of repeated recreational exposure to this drug are significantly less likely to produce high levels of IgG antibodies from the cocaine conjugate vaccine. The failure may be due to recreational cocaine exposure induction of a type 2 T-cell independent immune response. Such individuals will require improved vaccines and are poor candidates for the currently available vaccine.

Hapten-specific naïve B cells are biomarkers of vaccine efficacy against drugs of abuse

“…A recent study showed that cocaine users have serum IgM antibodies with very low affinity for cocaine (IC 50 ~ 4.5mM) and that the presence of cocaine-specific serum antibodies correlated with efficacy of a conjugate vaccine against cocaine [35]. Here, we found that the pre-immunization naïve B cell repertoire was mainly composed of naïve and memory B cells carrying IgM or IgD, which are characterized by low affinity and high avidity for antigens.…”

New Directions in Nicotine Vaccine Design and Use

“…No validated predictive biomarkers of nicotine vaccine response are currently available. Cocaine vaccine studies have identified possible effects of HLA type or the presence of low levels of preexisting spontaneous anticocaine antibodies (Orson et al, 2013) as factors in vaccine response. The ability of naive (prevaccination) B cells to bind an opioid hapten in vitro correlates with the magnitude of opioid-specific antibody response to vaccination in mice (M. Pravetoni, personal communication).…”

Can you vaccinate against substance abuse?

“…This ‘auto-immunization’ is an altered immune state with circulating IgM, which has a low affinity for morphine or cocaine, respectively, and does not provide any effective blockade to morphine’s or cocaine’s effects on the body such as euphoria [15,16]. More critically this IgM appears to be a marker of immune tolerance or suppression of an IgG response to these anti-addiction vaccines [17]. This IgM marker has so far only been demonstrated in humans given a cocaine vaccine and not in to nicotine in smokers, but in principle individuals with chronic exposure to opiates and possibly methamphetamine and other haptenated vaccines may develop this ‘auto-immunization’ and immune tolerance to subsequent vaccination.…”